The broad, long range objective of the proposed research is the definition at the molecular level of the mechanism(s) involved in drug resistance in Plasmodium. The proposal is based on previous results from our laboratory, as well as other groups, in which genes of have been identified in Plasmodium falciparum and P. berqhei, which show homology to the multidrug resistance (mdr) genes from other organisms and appear to be involved in parasite drug resistance. We propose an in vivo rodent malaria model, which includes naturally resistant strains of P. yoelii, as well as parasite lines with different profiles of drug resistance. The specific aims are: (1) To identify and characterize mdr homologous genes in the murine malaria parasite, P. yoelii and (2) To analyze the malaria mdr homologous genes in drug sensitive and drug resistant lines of the parasite. The working hypothesis is that P. yoelii will express mdr-like genes in both sensitive and resistant strains, and its product is related to the development of some multidrug resistance phenotypes. Understanding the mechanisms by which the parasites become resistant will provide the basis for better drug design and improved control of the disease.